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United States Patent |
5,527,916
|
Blacker
,   et al.
|
June 18, 1996
|
Pyranones
Abstract
A process for the separation of at least one isomer from a mixture of
isomers of a tetrahydropyran-2-one, having at least two chiral centers
which comprises selective reaction of at least one isomer with a reagent
catalyzed by a hydrolase enzyme whereby at least one isomer is
preferentially converted into a distinct chemical species from the other
isomers so that it is susceptible of separation by an appropriate chemical
or physical separation process in which the tetrahydropyran-2-one is of
Formula (1):
##STR1##
wherein: Z is --H or a protecting group susceptible of reaction with the
reagent under the influence of the enzyme; and
Y is formyl or protected formyl.
Inventors:
|
Blacker; Andrew J. (North Rigton, GB2);
Crosby; John (Bowden, GB2);
Herbert; John A. L. (Ramsbottom, GB2)
|
Assignee:
|
Zeneca Limited (London, GB2)
|
Appl. No.:
|
211043 |
Filed:
|
August 1, 1994 |
PCT Filed:
|
September 11, 1992
|
PCT NO:
|
PCT/GB92/01666
|
371 Date:
|
August 1, 1994
|
102(e) Date:
|
August 1, 1994
|
PCT PUB.NO.:
|
WO93/06236 |
PCT PUB. Date:
|
April 1, 1993 |
Foreign Application Priority Data
| Sep 20, 1991[GB] | 9120110 |
| Sep 20, 1991[GB] | 9120134 |
| Sep 20, 1991[GB] | 9120138 |
| Sep 20, 1991[GB] | 9120152 |
| Sep 20, 1991[GB] | 9120153 |
| Sep 20, 1991[GB] | 9120157 |
| Sep 20, 1991[GB] | 9120173 |
| Jun 04, 1992[GB] | 9211795 |
Current U.S. Class: |
548/200; 548/236; 548/311.1; 549/214; 549/218; 549/291 |
Intern'l Class: |
C07D 277/04; C07D 309/30 |
Field of Search: |
549/291,214,218
548/200,236,311.1
|
References Cited
U.S. Patent Documents
4625039 | Nov., 1986 | Jewell, Jr. et al. | 549/214.
|
Foreign Patent Documents |
0271432 | Jun., 1988 | EP.
| |
0428392 | May., 1991 | EP.
| |
0439779 | Aug., 1991 | EP.
| |
WO86/00307 | Jan., 1986 | WO.
| |
Other References
Cardani et al, S. Tetrahedron 46(20) pp. 7283-7288 (1990).
|
Primary Examiner: Ivy; C. Warren
Assistant Examiner: Owens; Amelia
Attorney, Agent or Firm: Cushman Darby & Cushman
Parent Case Text
This is a 371 of PCT/GB92/01666 filed Sep. 11, 1992 and a divisional
application of U.S. Ser. No. 07/946,194, filed Sep. 17, 1992, now U.S.
Pat. No. 5,443,971.
Claims
We claim:
1. A resolved isomer of the Formula (1):
##STR43##
wherein: Z is --H or a protecting group selected from the group consisting
of --PO.(OR.sup.3).sub.2, --CO.R.sup.3, --SO.OR.sup.3, --NO.sub.2 and
--CO.OR.sup.3 in which each R.sup.3 independently is optionally
substituted C.sub.1-12 -alkyl, optionally substituted C.sub.2-12 -alkenyl
or optionally substituted phenyl in which each of the alkyl and alkenyl
groups represented by R.sup.3 is optionally substituted by C.sub.1-6
-alkoxy, --Cl, --Br, --F, --OH, --CN, cyclohexyl, phenyl, --NHCOMe,
--N(SiMe.sub.3).sub.2 or --NR.sub.2 in which R is --H, C.sub.1-12 -alkyl,
C.sub.2-12 -alkenyl or phenyl and in which each of the phenyl groups
represented by R.sup.3 is optionally substituted by C.sub.1-6 -alkyl,
C.sub.1-6 -alkoxy, cyclohexyl, phenyl, --NO.sub.2, --OH, --CN, --Cl, --Br,
--F, --NHCOMe, --N(SiMe.sub.3).sub.2 or --NR.sub.2 ; and
Y is formyl or protected formyl selected from the group consisting of
--CH(OR).sub.2, --CH(SR).sub.2, --CH(OR)(SR), oxazolidine, imidazolidine,
thiazolidine, bisulphite, cyanohydrin, hydrazone, oxime,
O-acylcyanohydrin, O-tetrahydropyran-2-ylcyanohydrin, O--SiR.sup.3
cyanohydrin and
##STR44##
in which each R independently is --H, optionally substituted C.sub.1-12
-alkyl, optionally substituted C.sub.2-12 -alkenyl or optionally
substituted phenyl in which each of the alkyl and alkyl groups is
optionally substituted by C.sub.1-6 -alkoxy, --Cl, --Br, --F, --OH, --CN,
cyclohexyl, phenyl, --NHCOMe, --N(SiMe.sub.3).sub.2 or --NR.sub.2 in which
R is selected from --H, C.sub.1-12 -alkyl, C.sub.2-12 -alkenyl and phenyl
and in which each of the phenyl groups represented by R is optionally
substituted by C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, cyclohexyl, phenyl,
--NO.sub.2, --OH, --CN, --Cl, --Br, --F, --NHCOMe, --N(SiMe.sub.3).sub.2
and --NR.sub.2.
2. A resolved tetrahydropyran-2-one isomer is of Formula (14):
##STR45##
wherein: Z is --H or a protecting group selected from the group consisting
of --PO.(OR.sup.3).sub.2, --CO.R.sup.3, --SO.OR.sup.3, --NO.sub.2 and
--CO.OR.sup.3 in which each R.sup.3 independently is optionally
substituted C.sub.1-12 -alkyl, optionally substituted C.sub.2-12 -alkenyl
or optionally substituted phenyl in which each of the alkyl and alkenyl
groups represented by R.sup.3 is optionally substituted by C.sub.1-6
-alkoxy, --Cl, --Br, --F, --OH, --CN, cyclohexyl, phenyl, --NHCOMe,
--N(SiMe.sub.3).sub.2 or --NR.sub.2 in which R is --H, C.sub.1-12 -alkyl,
C.sub.2-12 -alkenyl or phenyl and in which each of the phenyl groups
represented by R.sup.3 is optionally substituted by C.sub.1-6 -alkyl,
C.sub.1-6 -alkoxy, cyclohexyl, phenyl, --NO.sub.2, --OH, --CN, --Cl, --Br,
--F, --NHCOMe, --N(SiMe.sub.3).sub.2 or --NR.sub.2 ; and
Y is formyl or protected formyl selected from the group consisting of
--CH(OR).sub.2, --CH(SR).sub.2, --CH(OR)(SR), oxazolidine, imidazolidine,
thiazolidine, bisulphite, cyanohydrin, hydrazone, oxime,
O-acylcyanohydrin, O-tetrahydropyran-2-ylcyanohydrin, O--SiR.sup.3
cyanohydrin and
##STR46##
in which each R independently is --H, optionally substituted C.sub.1-12
-alkyl, optionally substituted C.sub.2-12 -alkenyl or optionally
substituted phenyl in which each of the alkyl and alkyl groups is
optionally substituted by C.sub.1-6 -alkoxy, --Cl, --Br, --F, --OH, --CN,
cyclohexyl, phenyl, --NHCOMe, --N(SiMe.sub.3).sub.2 or --NR.sub.2 in which
R is selected from --H, C.sub.1-12 -alkyl, C.sub.2-12 -alkenyl and phenyl
and in which each of the phenyl groups represented by R is optionally
substituted by C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, cyclohexyl, phenyl,
--NO.sub.2, --OH, --CN, --Cl, --Br, --F, --NHCOMe, --N(SiMe.sub.3).sub.2
and --NR.sub.2.
3. A resolved tetrahydropyran-2-one isomer is of Formula (15):
##STR47##
wherein: Z is H or a protecting group selected from the group consisting
of --PO.(OR.sup.3).sub.2, --CO.R.sup.3, --SO.OR.sup.3, --NO.sub.2 and
--CO.OR.sup.3 in which each R.sup.3 independently is optionally
substituted C.sub.1-12 -alkyl, optionally substituted C.sub.2-12 -alkenyl
or optionally substituted phenyl in which each of the alkyl and alkenyl
groups represented by R.sup.3 is optionally substituted by C.sub.1-6
-alkoxy, --Cl, --Br, --F, --OH, --CN, cyclohexyl, phenyl, --NHCOMe,
--N(SiMe.sub.3).sub.2 or --NR.sub.2 in which R is --H, C.sub.1-12 -alkyl,
C.sub.2-12 -alkenyl or phenyl and in which each of the phenyl groups
represented by R.sup.3 is optionally substituted by C.sub.1-6 -alkyl,
C.sub.1-6 -alkoxy, cyclohexyl, phenyl, --NO.sub.2, --OH, --CN, --Cl, --Br,
--F, --NHCOMe, --N(SiMe.sub.3).sub.2 or --NR.sub.2 ; and
Y is formyl or protected formyl selected from the group consisting of
--CH(OR).sub.2, --CH(SR).sub.2, --CH(OR)(SR), oxazolidine, imidazolidine,
thiazolidine, bisulphite, cyanohydrin, hydrazone, oxime,
O-acylcyanohydrin, O-tetrahydropyran-2-ylcyanohydrin, O--SiR.sup.3
cyanohydrin and
##STR48##
in which each R independently is --H, optionally substituted C.sub.1-12
-alkyl, optionally substituted C.sub.2-12 -alkenyl or optionally
substituted phenyl in which each of the alkyl and alkyl groups is
optionally substituted by C.sub.1-6 -alkoxy, --Cl, --Br, --F, --OH, --CN,
cyclohexyl, phenyl, --NHCOMe, --N(SiMe.sub.3).sub.2, or --NR.sub.2 in
which R is selected from --H, C.sub.1-12 -alkyl, C.sub.2-12 -alkenyl and
phenyl and in which each of the phenyl groups represented by R is
optionally substituted by C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, cyclohexyl,
phenyl, --NO.sub.2, --OH, --CN, --Cl, --Br, --F, --NHCOMe,
'N(SiMe.sub.3).sub.2 and --NR.sub.2.
4. A resolved tetrahydropyran-2-one isomer is of Formula (16):
##STR49##
wherein: Z is --H or a protecting group selected from the group consisting
of --PO.(OR.sup.3).sub.2, --CO.R.sup.3, --SO.OR.sup.3, --NO.sub.2 and
--CO.OR.sup.3 in which each R.sup.3 independently is optionally
substituted C.sub.1-12 -alkyl, optionally substituted C.sub.2-12 -alkenyl
or optionally substituted phenyl in which each of the alkyl and alkenyl
groups represented by R.sup.3 is optionally substituted by C.sub.1-6
-alkoxy, --Cl, --Br, --F, --OH, --CN, cyclohexyl, phenyl, --NHCOMe,
--N(SiMe.sub.3).sub.2 or --NR.sub.2 in which R is --H, C.sub.1-12 -alkyl,
C.sub.2-12 -alkenyl or phenyl and in which each of the phenyl groups
represented by R.sup.3 is optionally substituted by C.sub.1-6 -alkyl,
C.sub.1-6 -alkoxy, cyclohexyl, phenyl, --NO.sub.2, --OH, --CN, --Cl, --Br,
--F, --NHCOMe, --N(SiMe.sub.3).sub.2 or --NR.sub.2 ; and
Y is formyl or protected formyl selected from the group consisting of
--CH(OR).sub.2, --CH(SR).sub.2, --CH(OR) (SR), oxazolidine, imidazolidine,
thiazolidine, bisulphite, cyanohydrin, hydrazone, oxime,
O-acylcyanohydrin, O-tetrahydropyran-2-ylcyanohydrin, O--SiR.sup.3
cyanohydrin and
##STR50##
in which each R independently is --H, optionally substituted C.sub.1-12
-alkyl, optionally substituted C.sub.2-12 -alkenyl or optionally
substituted phenyl in which each of the alkyl and alkyl groups is
optionally substituted by C.sub.1-6 -alkoxy, --Cl, --Br, --F, --OH, --CN,
cyclohexyl, phenyl, --NHCOMe, --N(SiMe.sub.3).sub.2 or --NR.sub.2 in which
R is selected from --H, C.sub.1-12 -alkyl, C.sub.2-12 -alkenyl and phenyl
and in which each of the phenyl groups represented by R is optionally
substituted by C.sub.1-6 alkyl, C.sub.1-6 -alkoxy, cyclohexyl, phenyl,
--NO.sub.2, --OH, --CN, --Cl, --Br, --F, --NHCOMe, --N(SiMe.sub.2).sub.2
and --NR.sub.2.
5. A resolved tetrahydropyran-2-one isomer is of Formula (17):
##STR51##
wherein: Z is --H or a protecting group selected from the group consisting
of --PO.(OR.sup.3).sub.2, --CO.R.sup.3, --SO.OR.sup.3, --NO.sub.2 and
--CO.OR.sup.3 in which each R.sup.3 independently is optionally
substituted C.sub.1-12 -alkyl, optionally substituted C.sub.2-12 -alkenyl
or optionally substituted phenyl in which each of the alkyl and alkenyl
groups represented by R.sup.3 is optionally substituted by C.sub.1-6
-alkoxy, --C.sub.1, --Br, --F, --OH, --CN, cyclohexyl, phenyl, --NHCOMe,
--N(SiMe.sub.3).sub.2 or --NR.sub.2 in which R is --H, C.sub.1-12 -alkyl,
C.sub.2-12 -alkenyl or phenyl and in which each of the phenyl groups
represented by R.sup.3 is optionally substituted by C.sub.1-6 -alkyl,
C.sub.1-6 -alkoxy, cyclohexyl, phenyl, --NO.sub.2, --OH, --CN, --Cl, --Br,
--F, --NHCOMe, --N(SiMe.sub.3).sub.2 or --NR.sub.2 ; and
Y is formyl or protected formyl selected from the group consisting of
--CH(OR).sub.2, --CH(SR).sub.2, --CH(OR) (SR), oxazolidine, imidazolidine,
thiazolidine, bisulphite, cyanohydrin, hydrazone, oxime,
O-acylcyanohydrin, O-tetrahydropyran-2-ylcyanohydrin, O--SiR.sup.3
cyanohydrin and
##STR52##
in which each R independently is --H, optionally substituted C.sub.1-12
-alkyl, optionally substituted C.sub.2-12 -alkenyl or optionally
substituted phenyl in which each of the alkyl and alkyl groups is
optionally substituted by C.sub.1-6 -alkoxy, --Cl, --Br, --F, --OH, --CN,
cyclohexyl, phenyl, --NHCOMe, --N(SiMe.sub.3).sub.2 or --NR.sub.2 in which
R is selected from --H, C.sub.1-12 -alkyl, C.sub.2-12 -alkenyl and phenyl
and in which each of the phenyl groups represented by R is optionally
substituted by C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, cyclohexyl, phenyl,
--NO.sub.2, --OH, --CN, --Cl, --Br, --F, --NHCOMe, --N(SiMe.sub.3).sub.2
and --NR.sub.2 except for (4S, 6R)
4-hydroxy-6-di(ethylthio)methyltetrahydropyran-2-one.
6. A racemate comprising the compounds of Formulae (14) and (17):
##STR53##
wherein: Z is --H or a protecting group selected from the group consisting
of --PO.(OR.sup.3).sub.2, --CO.R.sup.3, --SO.OR.sup.3, --NO.sub.2 and
--CO.OR.sup.3 in which each R.sup.3 independently is optionally
substituted C.sub.1-12 -alkyl, optionally substituted C.sub.2-12 -alkenyl
or optionally substituted phenyl in which each of the alkyl and alkenyl
groups represented by R.sup.3 is optionally substituted by C.sub.1-6
-alkoxy, --Cl, --Br, --F, --OH, --CN, cyclohexyl, phenyl, --NHCOMe,
--N(SiMe.sub.3).sub.2 or --NR.sub.2 in which R is --H, C.sub.1-12 -alkyl,
C.sub.2-12 -alkenyl or phenyl and in which each of the phenyl groups
represented by R.sup.3 is optionally substituted by C.sub.1-6 -alkyl,
C.sub.1-6 -alkoxy, cyclohexyl, phenyl, --NO.sub.2, --OH, --CN, --Cl, --Br,
--F, --NHCOMe, --N(SiMe.sub.3).sub.2 or --NR.sub.2 ; and
Y is formyl or protected formyl selected from the group consisting of
--CH(OR).sub.2, --CH(SR).sub.2, --CH(OR) (SR), oxazolidine, imidazolidine,
thiazolidine, bisulphite, cyanohydrin, hydrazone, oxime,
O-acylcyanohydrin, O-tetrahydropyran-2-ylcyanohydrin, O--SiR.sup.3
cyanohydrin and
##STR54##
in which each R independently is --H, optionally substituted C.sub.1-12
-alkyl, optionally substituted C.sub.2-12 -alkenyl or optionally
substituted phenyl in which each of the alkyl and alkyl groups is
optionally substituted by C.sub.1-6 -alkoxy, --Cl, --Br, --F, --OH, --CN,
cyclohexyl, phenyl, --NHCOMe, --N(SiMe.sub.3).sub.2 or --NR.sub.2 in which
R is selected from --H, C.sub.1-12 -alkyl, C.sub.2-12 -alkenyl and phenyl
and in which each of the phenyl groups represented by R is optionally
substituted by C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, cyclohexyl, phenyl,
--NO.sub.2, --OH, --CN, --Cl, --Br, --F, --NHCOMe, --N(SiMe.sub.3).sub.2
and --NR.sub.2.
7. A racemate comprising the compounds of the Formulae (15) and (16):
##STR55##
wherein: Z is --H or a protecting group selected from the group consisting
of --PO.(OR.sup.3).sub.2, --CO.R.sup.3, --SO.OR.sup.3, --NO.sub.2 and
--CO.OR.sup.3 in which each R.sup.3 independently is optionally
substituted C.sub.1-12 -alkyl, optionally substituted C.sub.2-12 -alkenyl
or optionally substituted phenyl in which each of the alkyl and alkenyl
groups represented by R.sup.3 is optionally substituted by C.sub.1-6
-alkoxy, --Cl, --Br, --F, --OH, --CN, cyclohexyl, phenyl, --NHCOMe,
--N(SiMe.sub.3).sub.2 or --NR.sub.2 in which R is --H, C.sub.1-12 -alkyl,
C.sub.2-12 -alkenyl or phenyl and in which each of the phenyl groups
represented by R.sup.3 is optionally substituted by C.sub.1-6 -alkyl,
C.sub.1-6 -alkoxy, cyclohexyl, phenyl, --NO.sub.2, --OH, --CN, --Cl, --Br,
--F, --NHCOMe, --N(SiMe.sub.3).sub.2 or --NR.sub.2 ; and
Y is formyl or protected formyl selected from the group consisting of
--CH(OR).sub.2, --CH(SR).sub.2, --CH(OR) (SR), oxazolidine, imidazolidine,
thiazolidine, bisulphite, cyanohydrin, hydrazone, oxime,
O-acylcyanohydrin, O-tetrahydropyran-2-ylcyanohydrin, O--SiR.sup.3
cyanohydrin and
##STR56##
in which each R independently is --H, optionally substituted C.sub.1-12
-alkyl, optionally substituted C.sub.2-12 -alkenyl or optionally
substituted phenyl in which each of the alkyl and alkyl groups is
optionally substituted by C.sub.1-6 -alkoxy, --Cl, --Br, --F, --OH, --CN,
cyclohexyl, phenyl, --NHCOMe, --N(SiMe.sub.3).sub.2 or --NR.sub.2 in which
R is selected from --H, C.sub.1-12 -alkyl, C.sub.2-12 -alkenyl and phenyl
and in which each of the phenyl groups represented by R is optionally
substituted by C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, cyclohexyl, phenyl,
--NO.sub.2, --OH, --CN, --Cl, --Br, --F, --NHCOMe, --N(SiMe.sub.3).sub.2
and --NR.sub.2.
Description
This invention relates to processes for the preparation of
tetrahydropyran-2-ones which involve a kinetic resolution stage for
producing at least one optically active isomer of a tetrahydro pyran-2-one
having at least two chiral centres from a mixture of isomers, such as a
cis or trans racemate or a mixture of cis and trans racemates, to certain
novel isomers, particularly single enantiomers, of the
tetrahydropyran-2-one, and to certain novel dihydropyran-2-ones and
pyran-2-ones.
Optically active materials such as tetrahydropyran-2-ones may be used as
intermediates in the manufacture of compounds such as pharmaceuticals,
agrochemicals and chemicals for use in electronics industry. The optically
active tetrahydropyran-2-ones of the present invention are particularly
useful as intermediates in the manufacture of HMG-CoA reductase
inhibitors. Available processes for the production of
tetrahydropyran-2-ones are typically lengthy, require reagents which are
expensive or difficult to handle on a large scale, give poor overall
yields, and do not give access to all optical isomers.
According to the present invention there is provided a process for the
separation of at least one isomer from a mixture of isomers of a
tetrahydropyran-2-one, having at least two chiral centres, which comprises
selective reaction of at least one isomer with a reagent catalysed by a
hydrolase enzyme whereby at least one isomer is preferentially converted
into a distinct chemical species from the other isomers so that it is
susceptible of separation by an appropriate chemical or physical
separation process in which the tetrahydropyran-2-one is of Formula (1):
##STR2##
wherein: Z is --H or a protecting group susceptible of reaction with the
reagent under the influence of the enzyme; and
Y is formyl or protected formyl.
The protecting group, Z, is preferably a readily displaceable protecting
group. Examples of suitable readily displaceable protecting groups include
--PO.(OR.sup.3).sub.2, --CO.R.sup.3 ; --SO.OR.sup.3 ; --NO.sub.2 and
--(CO).OR.sup.3 in which each R.sup.3 is independently optionally
substituted alkyl, optionally substituted alkenyl or optionally
substituted phenyl. Preferred examples of the protecting group, Z, include
benzoyl, --COCH.sub.3, --CO(n--C.sub.3 H.sub.7) and --(CO)OCH.sub.3.
Where the group represented by Y is protected formyl it is preferably of
the formula --CH(OR).sub.2, --CH(SR).sub.2 or --CH(OR)(SR) wherein each R
independently is --H, optionally substituted alkyl, optionally substituted
alkenyl or optionally substituted phenyl or two groups --OR or --SR
attached to the same carbon atom, together with the carbon atom to which
they are attached, form a 5- to 7-membered heterocycle. Examples of such
groups are:
##STR3##
in which each T is a divalent group. Examples of suitable groups
represented by T are --C.sub.2 H.sub.4 --, --(CH.sub.2).sub.3 --,
--CH(CH.sub.3)--CH(CH.sub.3)-- and --CH(Ph)--CH(Ph)--. Alternatively, the
formyl group may be protected by conversion into an oxazolidine,
imidazolidine, thiazolidine, bisulphite, O-substituted cyanohydrin such as
O-acyl, O-tetrahydropyran-2-yl and O--SiR.sup.3 in which R.sup.3 is as
hereinbefore defined, cyanohydrin, hydrazone or oxime derivative. It is
preferred that the formyl group is protected by conversion into an
oxazolidine.
Where R or R.sup.3 is or contains an alkyl group this is preferably
C.sub.1-12 -alkyl, more preferably C.sub.1-6 -alkyl and especially methyl,
ethyl, propyl or butyl.
Where R or R.sup.3 is or contains an alkenyl group this is preferably
C.sub.2-12 -alkenyl, more preferably C.sub.2-6 -alkenyl and especially
vinyl. Where any R or R.sup.3 is alkyl or alkenyl it may be in the form of
a straight or R.sup.3 branched chain.
Where the group represented by R or is optionally R.sup.3 is optionally
substituted alkyl or alkenyl, the substituent is preferably selected from
C.sub.1-6 -alkoxy; halogen, such as --Cl, --Br or --F; hydroxy; cyano;
--NR.sub.2 in which R is as hereinbefore defined such as --NMe.sub.2 ;
cyclohexyl; phenyl; and protected primary and secondary amino groups such
as --NHCOMe and --N(SiMe.sub.3).sub.2. Where the group represented by R or
R.sup.3 is optionally substituted phenyl, the substituent is preferably
selected from C.sub.1-6 -alkyl, especially methyl; C.sub.1-6 -alkoxy,
especially methoxy; cyclohexyl; phenyl; nitro; hydroxy; cyano; halogen,
especially Cl, Br, or F; --NR.sub.2 in which R is as hereinbefore defined
such as --NMe.sub.2 ; and protected primary and secondary amino groups
such as --NHCOMe and --N(SiMe.sub.3).sub.2.
Examples of particularly preferred groups represented by Y are CO.H,
--CH(OCH.sub.3).sub.2, --CH(OPh).sub.2, --CH(OC.sub.2 H.sub.5).sub.2,
--CH(SC.sub.2 H.sub.5).sub.2, --CH(OC.sub.2 H.sub.5)(SC.sub.2 H.sub.5),
##STR4##
or a formyl group protected by formation of an oxazolidine with
ethanolamine or by formation of an imidazolidine by reaction with
1,2-ethylenediamine, or by formation of a thiazolidine by reaction with a
2-aminoethanethiol.
The enzyme catalysed reaction is a kinetic resolution which means that the
reaction occurs because the enzyme catalyses the reaction of the reagent
with different isomers at different rates. A compound with two chiral
centres may consist of a mixture of four isomers i.e. two pairs of
enantiomers, and a suitable enzyme catalyses reaction of the reagent with
each isomer at a different rate so that over a period of time the
composition changes from a mixture of, for example 4 isomers to a mixture
of 3 isomers and a more distinct chemical species which can be separated
from the unchanged isomers by appropriate conventional separation
techniques; or one enantiomer of an enantiomer pair is similarly changed
to a distinct chemical species which may be similarly separated.
The nature of the reagent and the enzyme depends upon the nature of the
group --OZ and the stereochemistry of the isomer(s) with which the reagent
is to react. Where Z is --H the selective reaction is conveniently a
trans-esterification or esterification and the reagent is an ester or acid
capable of reaction with the group --OH when catalysed by the enzyme. In
this process the group --OH in the selected isomer(s) is converted into an
ester so that the isomer(s) is/are chemically distinct and can be readily
separated from the other isomer(s) in which Z is still --H. In this
reaction, the enzyme preferably causes the group R.sup.4 CO-- of an ester,
R.sup.4 COOR.sup.5 or an acid R.sup.4 COOH (in which R.sup.4 and R.sup.5
each independently is optionally substituted alkyl, alkenyl or aryl) to
react preferentially with a group --OZ in one, or all except one, isomer
in the mixture. It is preferred that the R.sup.4 CO-- portion is
preferentially attacked by the group 4 --OH in one, or all except one, of
the isomers in the mixture.
The alkyl and alkenyl groups represented by R.sup.4 and R.sup.5 are
preferably C.sub.1-18 -alkyl and C.sub.2-18 -alkenyl, more preferably
C.sub.1-6 -alkyl and C.sub.2-5 -alkenyl, especially C.sub.1-4 -alkyl and
vinyl and allyl respectively and may be straight or branched chain alkyl.
The aryl groups represented by R.sup.4 and R.sup.5 are preferably phenyl
or naphthyl each of which may be optionally substituted. Where the groups
R.sup.4 and R.sup.5 are optionally substituted the substituent may be
selected from any of those described above for R. R.sup.5 is preferably an
alkenyl group, more preferably a C.sub.2-3 -alkenyl group and especially
vinyl. R.sup.4 is preferably an alkyl group, more preferably a C.sub.1-4
-alkyl group and especially methyl, ethyl or n-propyl. The ester of the
formula R.sup.4 COOR.sup.5 may be an alkyl ester, e.g. an alkyl alkanoate,
such as methyl acetate, methyl butyrate or ethyl acetate or an alkyl
benzoate, such as methyl benzoate, but is preferably a non-reversible acyl
donor, especially an alkenyl ester, more preferably an alkenyl alkanoate
such as vinyl acetate or vinyl butyrate.
Scheme 1 illustrates a trans-esterification process where the reagent is
R.sup.4 COOR.sup.5 or an esterification process whre the reagent is
R.sup.4 COOH for a mixture of isomers of Formula (1) in which Z is --H and
Y is as hereinbefore defined:
Scheme 1
##STR5##
In Scheme 1, Compounds 1B, 1C & 1D are isomeric esters formed by
preferential esterification of the corresponding alcohol isomers in the
mixed isomer starting material and are distinct chemical species from the
unchanged alcohol, Compound 1A. The latter may be separated from the
former by any convenient means such as chromatography, solvent extraction,
crystallisation or distillation.
The trans-esterification and esterification reactions may be performed in a
two phase liquid medium comprising water and an immiscible organic liquid.
Where two phases are present the enzyme partitions predominantly into the
aqueous phase and thus the enzyme catalysed reaction occurs mainly in the
aqueous phase. In the aqueous phase the equilibrium position of the
trans-esterification and esterification reactions may be shifted resulting
in a decreased yield of the required product. Thus, the
trans-esterification or esterification reaction is preferably performed in
a single phase organic liquid medium which contains small amounts of
water.
By small amounts of water it is meant that water immiscible organic liquids
contain less than or equal to the amount of water required to saturate the
organic liquid and water miscible organic liquids contain less than 50%,
preferably less than 20% and especially less than 10% water.
When water is present in predominantly organic systems the concentration of
water may not be very meaningful and the system may be better defined
using the thermodynamic activity of water (Aw). Aw values may be measured
via relative humidity in an equilibrated gas phase as described in EP
64855A. Water under standard state conditions has by definition an Aw
value of 1. For the trans-esterification reaction the activity of water
(Aw) in the organic liquid is less than 1 and greater than 0.05,
preferably from 0.95 to 0.1.
The reaction medium may comprise one or more of the participating species,
such as the tetrahydropyran-2-one or the ester R.sup.4 COOR.sup.5 or the
acid R.sup.4 COOH or a substantially inert organic liquid or a mixture of
such liqiuds. Suitable inert organic liquids include a straight or
branched chain alkane, especially a C.sub.5-16 -alkane such as hexadecane,
iso-octane or hexane; an optionally substituted arene, especially an
optionally substituted benzene such as toluene or xylene; an optionally
substituted ether, especially a C.sub.1-5 -alkoxy-C.sub.1-5 -alkane such
as t-butoxymethane or ethoxyethane; a C.sub.4-8 -cyclic ether such as
tetrahydrofuran or 1,4-dioxane; a halogenated alkane, especially a
halogenated C.sub.1-3 -alkane such as dichloromethane, trichloromethane,
tetrachloromethane or 1,1,2-trichloroethane; a carboxylic acid, especially
a C.sub.1-3 -carboxylic acid such as ethanoic or propanoic acid; an alkyl
cyanide, especially a C.sub.1-3 -alkylcyanide such as acetonitrile; an
alkyl alkanoate, especially a C.sub.1-5 -alkyl C.sub.1-5 -alkanoate such
as i-propyl acetate, methyl butyrate or ethyl acetate; an alkyl benzoate,
especially a C.sub.1-5 -alkyl benzoate, such as methyl benzoate or ethyl
benzoate; an alkenyl alkanoate, especially a C.sub.2-5 -alkenyl C.sub.1-5
-alkanoate such as vinyl acetate or vinyl butyrate; or an optionally
branched alkanol, especially a C.sub.1-10 -alkanol, and more especially a
C.sub.1-6 -alkanol, such as butan-1-ol, butan-2-ol, t-butanol,
propan-2-ol, ethanol or methanol.
Where Z is a protecting group the selective reaction is conveniently a
hydrolysis and the reagent is a hydrolytic agent, such as water or an
alkanol, ROH in which R is as hereinbefore defined, which is capable of
replacing the protecting group Z by H when catalysed by the enzyme. In
this process the group OZ in the selected isomer(s) is converted into an
OH group so that the selected isomer(s) is/are chemically distinct and can
be readily separated from the other isomer(s) in which Z is still a
protecting group. In this reaction the enzyme preferably catalyses the
hydrolysis of one or more isomers in a mixture of isomers of Formula (1)
in which Z is a protecting group, such as --CO.R.sup.4 Scheme 2
illustrates the hydrolysis of a mixture of isomeric esters of Formula (1)
in which Z is --CO.R.sup.4 and R.sup.4 and Y are as hereinbefore defined:
Scheme 2
##STR6##
In Scheme 2, Compounds 1F, 1G and 1H are alcohols formed by preferential
hydrolysis of the corresponding esters in the starting material and these
are distinct chemical species from the unchanged ester, Compound 1E. The
former may be separated from the latter by any convenient means such as
chromatography, solvent extraction, crystallisation or distillation. Once
separated Compound 1E may be chemically hydrolysed to the corresponding
hydroxy compound.
The enzymatic hydrolysis reaction may be performed in a liquid medium such
as water, an organic liquid or a mixture thereof. Suitable organic liquids
for the hydrolysis are those described above for the trans-esterification.
Where the liquid medium comprises water or an alkanol, the water or
alkanol may form only a proportion of the liquid medium, e.g. from 1% to
50% thereof, depending on the equilibrium constant for the system, and may
be buffered at a pH from 4 to 10, preferably from 4 to 9 and especially
from 6 to 8. The buffer may be inorganic or organic and is preferably an
inorganic phosphate such as sodium or potassium phosphate or an organic
amine salt, such as the hydrochloride, acetate, phosphate or benzoate salt
of tri(hydroxymethylamino)methane.
The reaction medium for the trans-esterification, esterification or the
hydrolysis may further comprise components which stabilise the enzyme and
maximise its catalytic efficiency. Such components may comprise cations,
especially H.sup.+ and H.sub.3 O.sup.+ ; alkali metal cations such as
Li.sup.+, Na.sup.+ and K.sup.+ ; alkaline earth cations such as Mg.sup.2+
and Ca.sup.2+, Group III metal cations such as Al.sup.3+ ; transition
metal cations such as Zn.sup.2+, Fe.sup.2+, Cu.sup.2+, Co.sup.2+ and
Ni.sup.2+ ; and/or ammonium and substituted ammonium cations such as
NR.sub.4.sup.+ in which each R independently is as hereinbefore defined.
Other suitable components may comprise anions, especially halides such as
F.sup.-, Cl.sup.-, Br.sup.- and I.sup.- ; oxyphosphorus anions such as
HPO.sub.4.sup.2- and PO.sub.4.sup.3- ; oxysulphur anions such as
SO.sub.4.sup.2- ; oxynitrogen anions such as NO.sub.3.sup.- ; OH.sup.- ;
CO.sub.3.sup.2- and/or organic anions such as formate, acetate, oxalate,
tartrate, malonate or succinate. The preferred cations and anions may be
used in combination or as salts with other anions and cations,
respectively. Salts containing these ions may be employed undissolved in
the reaction medium in order to change the state of hydration and thus the
activity of water in the medium. For example when sodium carbonate
decahydrate is added to the reaction medium it becomes sodium carbonate
monohydrate by losing 9 equivalents of water, in this way a known amount
of water may be added to the reaction medium.
To this end the salts may be hydrated salts or mixtures of anhydrous and
hydrated salts (see Biochim, Biophys Acta (1991) 1078, 326). The
hydrolysis medium may also contain antioxidants such as ascorbates or
thiols, such as dithiothreitol, 2,3-dimethylpropanethiol, ethanethiol and
cysteine.
The trans-esterification, esterification and hydrolysis reactions may be
performed at temperatures from 0.degree. C. to 100.degree. C., preferably
from 10.degree. C. to 60.degree. C. more preferably from 25.degree. C. to
60.degree. C. and especially from 30.degree. C. to 60.degree. C. During
the course of the hydrolysis reaction an inorganic base, preferably an
alkali metal hydroxide such as sodium hydroxide, may be added to maintain
the pH of the reaction mixture. The reaction medium may be agitated by
appropriate methods such as stirring, shaking or sonicating.
The hydrolase enzyme is preferably an esterase, lipase, nitrilase, amidase,
peptidase, glycosidase or phosphatase derived from microbial, animal or
plant sources. Especially preferred enzymes are Chromobacterium viscosum
lipase from Biocatalysts Ltd, AMANO P lipase from Amano Pharmaceuticals
(AMANO is a trade mark of Amano Pharmaceuticals), Pseudomonas fluorescens
lipase from Biocatalysts or Fluka Chemie AG, Mucor miehi strain such as
NOVO IM60 and NOVO lypozyme from Novo Industrie (NOVO is a trade mark of
Novo Industrie) or Lipoprotein lipase from Pseudomonas species, from
Boehringer Mannheim GmbH or Fluka Chemie AG.
Suitable forms are microbial whole cell preparations or fractions derived
from microbial, plant and animal tissues containing the required hydrolase
activities. Such fractions include secreted enzymes, broken cells,
cell-free extracts and purified hydrolase enzymes. The hydrolase enzyme
may be prepared and used in the reaction as a lyophilised solid or
water-containing liquid. When the hydrolase enzyme is prepared as a
lyophilised solid it may further comprise components to stabilise the
enzyme system and maximise its catalytic activity and antioxidants as
described above.
The lyophilised solid may further comprise organic additives such as
sugars, preferably glucose, mannose or trehalose; or polyols such as
polyethyleneglycol; or detergents such as alkylammonium salts or
alkylsulphonate salts. The hydrolase enzyme may be coated, for example by
passive adsorption onto an inorganic or organic support material or
covalently bonded onto an inorganic or organic support material. The
inorganic support material may be a powdered or beaded silicate; an
infusorial material, such as diatomaceous earth; zeolite; montmorillonite
clay; or finely divided carbon such as charcoal or a polyphosphazene. A
preferred inorganic support material is a beaded glass, sand, silica gel;
a diatomaceous earth such as CELITE (CELITE is a trade mark of Johns
Manville Corporation); a molecular sieve (e.g. 4A); or charcoal. A
convenient organic support is a resin such as EUPERGIT C (EUPERGIT is a
trade mark of Rohm Pharma); an ionic exchange resin; a polysaccharide; a
polyacrylamide; a protein; a nucleic acid; a lipid; a detergent capable of
forming micelles; or a liposome. A preferred organic support material is
an anionic exchange resin or a cellulosic material such as SEPHAROSE
(SEPHAROSE is a trade mark of Pharmacia, Sweden).
The hydrolase enzyme may be prepared for use in the hydrolysis reaction as
a stock solution in an aqueous liquid medium containing components which
stabilise, maximise its catalytic activity and prevent its oxidation as
described above. The same stock solution may be freeze dried at a
temperature from -70.degree. C. under vacuum until almost dry to give a
hydrolase enzyme residue which is suitable for use in the
trans-esterification or esterification reactions. However, it is important
that the reaction medium for the trans-esterification and esterification
reactions contains at least some water otherwise the hydrolase enzyme is
ineffective as a trans-esterification or esterification catalyst. Thus
either the enzyme residue must contain some water of water must be added
to the trans-esterification or esterification medium.
A compound of Formula (1) in which Y is protected formyl such as
--CH(OR.sup.3).sub.2 may be prepared a) by reaction of the corresponding
compound in which Y is --CHO with an alcohol, R.sup.3 OH in which R.sup.3
is as hereinbefore defined, in the presence of dry hydrogen chloride or b)
by reaction of a compound of Formula (1) in which Y is --CHX.sub.2 with
R.sup.3 OH in the presence of a silver salt such as silver nitrate. A
compound of Formula (1) in which Y is protected formyl such as
--CH(SR.sup.3).sub.2 may be prepared by reaction of the corresponding
compound in which Y is --CHO with a thiol, R.sup.3 SH in which R.sup.3 is
as hereinbefore defined, in the presence of BF.sub.3.Et.sub.2 O. A
compound of Formula (1) in which Y is protected formyl such as
--CH(OR.sup.3)(SR.sup.3) may be prepared by reaction of the corresponding
compound in which Y is --CHO with a mixture of alcohol, R.sup.3 OH and
thiol R.sup.3 SH in which R.sup.3 is as hereinbefore defined.
Compounds of Formula (1) in which Y is protected formyl such as
--CH(OR.sup.3).sub.2, --CH(SR.sup.3).sub.2 or --CH(OR.sup.3)(SR.sup.3) in
which the R.sup.3 groups are joined to form a 5- to 7-membered heterocycle
may be formed by reaction of the corresponding compound of Formula (1) in
which Y is --CHO with a diol such as ethan-1,2-diol, a dithiol such as
propan-1,3-dithiol or a hydroxythiol such as 2-hydroxyethanethiol. A
compound of Formula (1) in which Y is oxazolidinyl, imidazolidinyl or
thiazolidinyl, i.e. a protected formyl group, may be prepared by reaction
of the corresponding compound of Formula (1) in which Y is --CO.H or
--CHX.sub.2 (in which X is halogen) with a 1-hydroxy-2-amino alkane such
as an ethanolamine, or a 1,2-diamino alkane such as an ethylenediamine, or
a 1-thiol-2-aminoalkane such as an aminoethanethiol, respectively. Where
the formyl group is protected by conversion into a bisulphite,
cyanohydrin, an O-substituted cyanohydrin, hydrazone or oxime derivative
these may be formed by reaction of the formyl compound with sodium
bisulphite, hydrogen cyanide, acetonecyanohydrin, Me.sub.3 SiCN/KCN,
hydrazines or hydroxylamines respectively.
The formyl group of compounds of Formulae (2) and (3) in which Y is formyl
and of Formula (10) may also be protected as described above. The
reactions to protect the formyl group form a further feature of the
present invention.
The 4-hydroxy group, in the the compound of Formula (1) in which Z is H,
may be protected for example by reaction with a compound of formula Z--X
(wherein Z is as hereinbefore defined except --H and --NO.sub.2 and X is
halogen, especially --Cl or --Br). Compounds of Formula (1) in which Z is
--NO.sub.2 may be prepared by reaction of the corresponding compound of
Formula (1) in which Z is mesyl with a tetraalkylammonium nitrate. Further
details of reactions for the preparation of --OZ compounds in which Z is a
protecting group are described in `Protective Groups in Organic
Synthesis`, T. W. Greene and P. G. M. Wuts published by Wiley & Sons 2nd
Edition (1991).
According to a further feature of the present invention there is provided a
process for the preparation of a tetrahydropyran-2-one of the Formula (1):
##STR7##
by reduction of a dihydropyran-2-one of Formula (2):
##STR8##
wherein: Y and Z are as hereinbefore defined.
This process may be performed by chemical reduction, where the compound of
Formula (2) preferably in a liquid medium, is reacted with hydrogen in the
presence of a catalyst. The liquid medium is preferably an organic liquid,
and more preferably an alcohol, especially a lower alkanol such as
ethanol, n-propanol or isopropanol or water or a mixture of water and
lower alkanol such as water/ethanol or an ester such as ethylacetate or
isopropylacetate. Suitable catalysts are metal catalysts preferably those
where the metal is from Group VIII of the Periodic Table. The catalyst is
preferably a finely divided metal or is a metal carried on a support such
as carbon or aluminium oxide. An especially preferred catalyst is Raney
nickel. The process is preferably performed at a temperature from
0.degree. C. to 120.degree. C., more preferably from 10.degree. C. to
80.degree. C. and especially from 20.degree. C. to 50.degree. C. The
process is conveniently carried out at the boiling point of the liquid
medium and at a pressure from 1.times.10.sup.4 Pa to 1.times. 10.sup.6 Pa,
preferably from 5.times.10.sup.4 Pa to 5.times.10.sup.5 Pa and especially
at from 8.times.10.sup.4 Pa to 2.times.10.sup.5 Pa. The process is
preferably continued until substantially all the starting material is
consumed which may be detected by chromatographic analysis. The product
may be isolated by removing the catalyst by filtration and evaporation of
the liquid medium. The product may be purified by any convenient means
such as distillation or crystallisation.
Where dihydropyran-2-ones of Formula (2) are already optically resolved at
the 6-position chemical reduction of the double bond between the 3- and
4-positions with cis- or trans-control fixes the stereochemistry at the
4-position and individual enantiomers can be obtained. For example with
cis-control enantiomers of Formulae (1J) or (1K) are obtained and with
trans-control, enantiomers of Formulae (1I) or (1L) can be obtained.
However, where dihydropyran-2-ones of Formula (2) are racemic, chemical
reduction with no cis-trans selectivity, produces a mixture of isomers of
Formulae (1I), (1J), (1K) and (1L):
##STR9##
Separation of a mixture of isomers of Formulae (1I), (1J), (1K) and (1L)
may be achieved by reacting the mixture with optically active
.alpha.-methylbenzylamine to form the corresponding diastereomeric
.alpha.-methylbenzylamide derivatives. The .alpha.-methylbenzylamide
derivatives may be separated by any convenient means such as
chromatography or crystallisation. After separation each
.alpha.-methylbenzylamide derivative is firstly hydrolysed and then
dehydrated to reform the individual isomers of Formulae (1I) to (1L).
According to a further feature of the present invention there is provided a
process for the preparation of a dihydropyran-2-one of the Formula (2):
##STR10##
by reduction of a pyran-2-one of the Formula (3):
##STR11##
wherein: Y and Z are as hereinbefore defined.
The process may be performed by chemical reduction, where the compound of
Formula (3) preferably in a liquid medium, is reacted with hydrogen in the
presence of a catalyst. The liquid medium is preferably an organic liquid
and especially an alkanol such as ethanol, or propanol or an ester such as
ethylacetate. Suitable catalysts are metal catalysts preferably where the
metal is from Group VIII of the Periodic Table. The catalyst is preferably
a finely divided metal or metal supported on a carbon or aluminium oxide
support and is optionally modified by pre-treatment before use in the
process. The catalyst is preferably palladium on carbon with a metal
loading of from 0.5 to 10% by weight preferably from 1 to 5% by weight.
The process is preferably performed at a temperature from 0.degree. C. to
80.degree. C., preferably from 15.degree. C. to 50.degree. C., especially
from 20.degree. C. to 30.degree. C. The process is preferably performed at
a pressure from 1.times.10.sup.4 Pa to 1.times.10.sup.7 Pa, more
preferably from 1.times.10.sup.5 Pa to 1.times.10.sup.7 Pa. The process is
preferably continued until all the starting material is consumed. The
product may be isolated by removing the catalyst by filtration and
evaporation of the liquid medium. The product may be purified by any
convenient means such as distillation or crystallisation.
According to the present invention there is provided a process for the
resolution of dihydropyran-2-ones of the Formula (2):
##STR12##
which comprises a selective reaction of one enantiomer with a reagent
catalysed by a hydrolase enzyme whereby the enantiomer is preferentially
converted into a distinct chemical species from the other enantiomer so
that it is susceptible of separation by an appropriate chemical or
physical separation process, wherein Y and Z are as hereinbefore defined.
The conditions for trans-esterification, esterification and hydrolysis
reactions described above for the resolution of compounds of Formula (1)
are applicable to the resolution of compounds of Formula (2); although the
especially preferred enzymes for the resolution of the compounds of
Formula (2) are Pseudomonas fluorescens lipases from Biocatalysts or Fluka
Chemie, Chromobacterium viscosum lipase from Biocatalysts, Candida
cylindracae from Biocatalysts, Fluka Chemie or Sigma, Mucor Miehi from
Biocatalysts or Fluka Chemie and Lipoprotein lipase from Boehringer
Mannhelm or Fluka Chemie. The process may be illustrated by the following
schemes whereby a racemate of Formula (2) may be resolved.
##STR13##
The products of these reactions may be separated by standard methods such
as solvent extraction, chromatography or crystallisation.
According to a further feature of the present invention there is provided a
process for the preparation of a tetrahydropyran-2-one of the Formula (1):
##STR14##
by reduction of a pyran-2-one of the Formula (3):
##STR15##
wherein: Y and Z are as hereinbefore defined.
The process may be performed by chemical reduction where the compound of
Formula (3) is reacted in a liquid medium with hydrogen in the presence of
a catalyst. The liquid medium is preferably an organic liquid and more
preferably an alkanol such as methanol, ethanol, n-propanol or n-butanol
or an ester such as ethyl acetate. Alternatively, the liquid medium may be
water or a mixture of water and alkanol such as water/ethanol. Suitable
catalysts are metal catalysts preferably those where the metal is from
Group VIII of the Periodic Table. The catalyst is preferably a finely
divided metal or a metal carried on a support such as carbon, more
preferably Raney Nickel. The process is preferably performed at a
temperature from 20.degree. C. to 130.degree. C. and more preferably from
50.degree. C. to 100.degree. C. The process may be conveniently carried
out at the boiling point of the liquid medium.
The process is performed at a pressure from 1.times.10.sup.4 Pa to
1.times.10.sup.6 Pa, preferably from 5.times.10.sup.4 Pa to
5.times.10.sup.5 Pa and especially from 8.times.10.sup.4 Pa to
2.times.10.sup.5 Pa. The process is preferably continued until
substantially all the starting material is consumed. The product is
isolated by removing the catalyst by filtration and evaporation of the
liquid medium. The product is purified by any convenient means such as
chromatography, distillation or crystallisation.
The hydrogenation of the pyran-2-one of Formula (3) to the
tetrahydropyran-2-one of Formula (1) may be carried out in two stages
without isolation of the intermediate dihydropyan-2-one of Formula (2),
the first stage in the presence of a more selective catalyst, such as
palladium on carbon and the second stage in the presence of a less
selective catalyst, such as Raney nickel.
According to a further feature of the present invention there is provided a
process for the preparation of a pyran-2-one of the Formula (3) in which Y
is formyl by reaction of a pyran-2-one of the Formula (4):
##STR16##
firstly with pyridine and secondly with a mixture of a nitroso compound
and a base, wherein:
Z is as hereinbefore defined; and
X is halogen.
The halogen represented by X is preferably --Cl, --Br, --I, more preferably
--Br.
This process may be performed by reaction of a compound of Formula (4)
firstly with pyridine and secondly with a mixture of a nitroso compound
and a base in a liquid medium. The liquid medium is preferably an aqueous
alkanol, more preferably aqueous ethanol. The nitroso compound is
preferably an aromatic nitroso compound such as
4-nitroso-N,N-dimethylaniline. The base is preferably an inorganic base
such as potassium carbonate. The process is preferably carried out at a
temperature from -10.degree. C. to 50.degree. C. more preferably from
0.degree. C. to 30.degree. C. The process is continued until substantially
all the starting material is consumed. The intermediate "pyranyl N-oxide"
is isolated by filtration of the reaction mixture and the pyran-2-one of
Formula (3) in which Y is formyl is liberated by acidifying with an
aqueous acid such as hydrochloric acid and extracting with an organic
solvent followed by evaporation. The product is purified by chromatography
as hereinbefore described.
According to a further feature of the present invention there is provided a
process for the preparation of a pyran-2-one of the Formula (3) in which Y
is formyl by oxidation of a pyran-2-one of the Formula (7):
##STR17##
wherein: Z is as hereinbefore defined.
This process may be performed by oxidation of a compound of Formula (7) in
a liquid medium with an oxidising agent. The liquid medium is preferably
an organic liquid more preferably an ether such as dioxan. The oxidising
agent is preferably selenium dioxide.
The process is preferably carried out at a temperature from 125.degree. C.
to 250.degree. C. and more preferably from 160.degree. C. to 200.degree.
C. The process is preferably carried out under pressure in a sealed
vessel.
The process is continued until substantially all the starting material is
consumed. The product is isolated by filtering the reaction mixture to
remove the residual solids followed by evaporation of the liquid medium.
The product may be purified by any convenient means such as
chromatographing from a silica column using a mixture of methylene
chloride/methanol as eluent.
According to a further feature of the present invention there is provided a
process for the preparation of a pyran-2-one of the Formula (4):
##STR18##
by removal of a group W from a pyran-2-one of the Formula (5):
##STR19##
wherein: W is --COT.sup.1 in which T.sup.1 is an optionally substituted
hydrocarbon group, --CHX.sub.2, --CH.sub.2 X in which X is halogen; and
Z is as hereinbefore defined.
In pyran-2-ones of Formula (5) W is preferably --COC.sub.1-2 -alkyl which
may be optionally substituted by halogen.
The present process may be performed by heating the pyran-2-one of Formula
(5) in a liquid medium in the presence of an acid. The acid is preferably
an inorganic acid, more preferably H.sub.2 SO.sub.4. The process is
preferably performed at a temperature from 50.degree. C. to 200.degree.
C., more preferably at from 80.degree. C. to 150.degree. C. and especially
at from 80.degree. C. to 135.degree. C. The process is preferably
continued until all the starting material is consumed. The product may be
isolated by neutralising the reaction mixture and extracting with a
solvent and evaporating the solvent. The product may be purified by any
convenient method such as distillation or crystallisation.
The removal of a group W is not limited to the present pyran-2-one of
Formula (5) and may be conveniently carried out at any stage in the
overall process, i.e. if a pyran-2-one of Formula (3) or (6) below carries
a group W in the 3-position this may be removed under similar conditions
to those described above.
According to a further feature of the present invention there is provided a
process for the preparation of a pyran-2-one of the Formula (5):
##STR20##
by halogenation of a pyran-2-one of the Formula (6):
##STR21##
wherein: W, X and Z are as hereinbefore defined.
The present process may be performed by halogenation of a pyran-2-one of
Formula (6) in a liquid medium with a halogenating agent, optionally in
the presence of ultraviolet light and optionally in the presence of an
organic peroxide to initiate the reaction.
The liquid medium is preferably an organic liquid which either does not
itself undergo halogenation under the reaction conditions or which is
already full halogenated. The organic liquid is preferably a haloalkane
such as tetrachloromethane or hexachloroethane. The halogenating agent is
preferably an N-halosuccinimide such as N-chlorosuccinimide for
chlorination, N-bromosuccinimide for bromination.
Where an organic peroxide is used to initiate the reaction it is preferably
an aromatic peroxide such as benzoyl peroxide or an aliphatic peroxide
such as t-butyl hydroperoxide.
The process is preferably carried out at a temperature from 0.degree. C. to
100.degree. C., preferably from 30.degree. C. to 80.degree. C. and more
preferably from 50.degree. C. to 80.degree. C. The reaction is continued
until substantially all the starting material has been consumed. The
product is isolated by evaporation of the liquid medium and purified by
any convenient means such as column chromatography.
According to a further feature of the present invention there is provided a
process for the preparation of a pyran-2-one of the Formula (8):
##STR22##
by halogenation of a compound of the Formula (5):
##STR23##
wherein; W, X and Z are as hereinbefore defined.
This process may be performed under the conditions described above for
halogenation of a compound of Formula (6).
According to a further feature of the present invention there is provided a
process for the preparation of a pyran-2-one of Formula (3) in which Y is
--CH(OR).sub.2 by reaction of a pyran-2-one of Formula (8) in which Z is
as hereinbefore defined, W is --H and X is halogen with a compound ROH
wherein R is as hereinbefore defined in the presence of a silver salt. X
is preferably --Cl or --Br, ROH is preferably an alkanol such as methanol
or ethanol and silver salt is preferably silver nitrate. The process is
preferably carried out at a temperature from 20.degree. C. to 100.degree.
C. and is continued until substantially all the starting material is
consumed. The product may be isolated by removal of the compound ROH and
may be purified by any convenient means such as chromatograhpy.
According to a further feature of the present invention there is provided a
process for the preparation of a pyran-2-one of the Formula (10):
##STR24##
by hydrolysis of a compound of the Formula (8):
##STR25##
wherein; W, X and Z are as hereinbefore defined.
This process may be performed by hydrolysis of the compound of Formula (2)
in a liquid medium. The liquid medium is preferably an alkanol such as
methanol, ethanol or isopropanol or water or a mixture of alkanol and
water. The hydrolysis may be effected in a number of ways by adding:
i) an acid, preferably an inorganic acid such as sulphuric acid or
hydrochloric acid;
ii) a base preferably an inorganic base such as sodium or potassium
hydroxide;
iii) by adding as silver nitrate; or
iv) a buffer to maintain the pH at approximately 7 to the compound of
Formula (2) in the liquid medium. The process is preferably carried out at
a temperature from 0.degree. C. to 150.degree. C. and more preferably from
50.degree. C. to 120.degree. C. and conveniently at the boiling point of
the liquid medium. The process is continued until substantially all the
starting material is consumed. The product is isolated by neutralisation
of the reaction mixture, extraction with an organic liquid, separation and
evaporation. The product is purified by any convenient means such as
distillation or column chromatography.
According to a further feature of the present invention there is provided a
process for the preparation of a pyran-2-one of the Formula (11):
##STR26##
by hydrolysis of a pyran-2-one of the Formula (5):
##STR27##
wherein; W, X and Z are as hereinbefore defined.
This process may be performed by hydrolysis of the compound of Formula (5)
in a liquid medium.
The liquid medium is preferably an alkanol such as methanol, ethanol or
isopropanol or water or a mixture of alkanol and water. The hydrolysis may
be effected in a number of ways by adding:
i) an acid. preferably an inorganic acid such as sulphuric acid or
hydrochloric acid:
ii) a base preferably an inorganic base such as sodium or potassium
hydroxide;
iii) by adding silver nitrate; or
iv) a buffer to maintain the pH at approximately 7 to the compound of
Formula (5) in the liquid medium. The process is preferably carried out at
a temperature from 0.degree. C. to 150.degree. C. and more preferably from
50.degree. C. to 120.degree. C. and conveniently at the boiling point of
the liquid medium.
The process is continued until substantially all the starting materials are
consumed. The product is isolated by neutralisation of the reaction
mixture, extraction with an organic liquid, separation and evaporation.
The product is purified by any convenient means such as distillation or
column chromatography.
According to a further feature of the present invention there is provided a
process for the preparation of a pyran-2-one of the Formula (10):
##STR28##
by oxidation of a pyran-2-one of the Formula (11):
##STR29##
wherein: W and Z are as hereinbefore defined.
This process may be performed under the oxidation conditions described
above for Formula (7).
According to a further feature of the present invention there is provided a
process for the preparation of a pyran-2-one of the Formula (7) by removal
of a group W from a pyran-2-one of Formula (6) wherein W and Z are as
hereinbefore defined. The removal of the group W may be performed under
the conditions described above for removal of the group W from the
pyran-2-one of Formula (5).
According to a further feature of the present invention there is provided a
process for the preparation of a pyran-2-one of Formula (4) by
halogenation of a pyran-2-one of Formula (7). The halogenation may be
performed under the conditions described above for halogenating the
pyran-2-one of Formula (6).
Halogenation of the pyran-2-one of Formula (6) in which W is --H to give
the corresponding pyran-2-one of Formula (5) in which W is --H or
halogenation of the pyran-2-one of Formula (5) in which W is --H to give
the corresponding pyran-2-one of Formula (8) in which W is --H or
halogenation of the pyran-2-one of Formula (8) in which W is --H to give
the corresponding pyran-2-one of Formula (9) in which W is --H may be
performed under the conditions described above for halogenating the
pyran-2-one of Formula (6).
Pyran-2-ones of Formula (5) where X is --I may also be prepared from
pyran-2-ones of Formula (5) where X is --Br by halogen exchange in a
liquid medium with iodide optionally in the presence of a phase transfer
catalyst. The phase transfer catalyst is preferably a tetraalkyl ammonium
halide such as tetrabutylammonium bromide. The liquid medium is preferably
an organic liquid, more preferably a ketone such as acetone or
methylethylketone or a lower alkanol such as ethanol or isopropanol. The
iodide is preferably an inorganic iodide such as potassium or sodium
iodide. This process forms a further aspect of the present invention.
The pyran-2-one of Formula (5) in which W is --H and Z is --H may be
prepared by reaction of an acid chloride of formula XCH.sub.2 COCl with
keten, followed by cyclisation of the intermediate dioxohexanoic acid
chloride to the compound of Formula (5).
The pyran-2-one of Formula (5) in which W is --COCH.sub.2 X and Z is --H
may be prepared by the self-condensation of 2 equivalents of a beta-keto
ester of the formula XCH.sub.2 COCH.sub.2 COOEt, in which Y is as
hereinbefore defined, in a liquid medium such as chloroform in the
presence of phosphorus pentoxide, further details are provided in Izv.
Akad. Nauk. SSR, Ser. Khim. (1982) 1657.
According to the a further feature of present invention there is provided a
process for the preparation of a compound of the Formula (13):
##STR30##
by the elimination of ZOH from a compound of Formula (1):
##STR31##
wherein: Y and Z are as hereinbefore defined.
A particular utility of the compounds of Formula (13) is that they permit
synthesis of trans isomers of compounds of Formula (1) from the cis
isomers or from cis/trans mixtures, for example:
##STR32##
wherein R' is any of the groups hereinbefore defined for Z or an
optionally substituted C.sub.1-12 -alkyl.
For compounds of Formula (1) in which Z is --H the process may be performed
by dehydrating the compound of Formula (1) in a liquid medium in the
presence of a dehydration catalyst. The liquid medium is preferably an
organic liquid, more preferably an aromatic hydrocarbon such as toluene or
xylene. Suitable dehydration catalysts are sulphonic acids preferably
aromatic sulphonic acids such as p-toluenesulphonic acid. The process is
preferably performed at a temperature from 20.degree. C. to 150.degree.
C., more preferably from 50.degree. C. to 150.degree. C. and especially at
the boiling point of the liquid medium. The reaction is continued until
substantially all the starting material is consumed. After washing to
remove the catalyst the product is isolated by evaporation of the liquid
medium and is purified by any convenient means such as crystallisation,
solvent extraction or chromatography.
For compounds of Formula (1) in which Z is for example --SO.OR.sup.3,
--(CO)OR.sup.3, --CO.R.sup.3 or --PO.(OR.sup.3).sub.2 the process may be
performed by eliminating HOSO.sub.2 R.sup.3, HO(CO)OR.sup.3, HOCO.R.sup.3
or HOPO.(OR.sup.3).sub.2 respectively from the compound of Formula (1) by
reaction with a base in a liquid medium. Suitable bases are organic
nitrogen bases such as triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), metal alkoxides,
preferably alkali metal alkoxides such as sodium ethoxide or potassium
t-butoxide or inorganic bases such as sodium carbonate. The liquid medium
is preferably an organic liquid, more preferably a halocarbon such as
dichloromethane, an aromatic hydrocarbon such as toluene or an anhydrous
dipolar aprotic liquid such as dimethylformamide (DMF) and
dimethylsulphoxide (DMSO). The process may optionally be performed in the
presence of a phase transfer catalyst. Suitable phase transfer catalysts
are alkyl ammonium halides such as tetrabutylammonium bromide and
tetramethylammonium bromide or chloride. The process is preferably
performed at a temperature from 20.degree. C. to 200.degree. C., more
preferably at 30.degree. C. to 100.degree. C. The reaction is continued
until substantially all the starting material is consumed. After treatment
to remove residual base, the product may be isolated by evaporation of the
liquid medium and purified as above.
Elimination of ZOH from an individual enantiomer of Formula (1) by the
above process produces a single optical isomer of Formula (13).
In compounds of Formula (1) in which Z is --H the 4-hydroxy group may be
converted to a sulphonate ester group by reaction with the corresponding
sulphonyl chloride, such as 4-toluenesulphonyl chloride in the presence of
pyridine or methanesulphonyl chloride in the presence of triethylamine.
According to a further feature of the present invention there is provided a
resolved isomer of the Formula (1) wherein Z and Y are as hereinbefore
defined.
A preferred resolved tetrahydropyran-2-one isomer of Formula (1) is of
Formula (14):
##STR33##
wherein: Z is --H or a protecting group; and
Y is formyl or protected formyl.
A further preferred resolved tetrahydropyran-2-one isomer of Formula (1) is
of Formula (15):
##STR34##
wherein: Z is --H or a protecting group; and
Y is formyl or protected formyl.
A further preferred resolved tetrahydropyran-2-one isomer of Formula (1) is
of Formula (16):
##STR35##
wherein: Z is --H or a protecting group; and
Y is formyl or protected formyl.
A further preferred resolved tetrahydropyran-2-one isomer of Formula (1) is
of Formula (17):
##STR36##
Z is --H or a protecting group; and Y is formyl or protected formyl,
except for (4S,6R) 4-hydroxy-6-di(ethylthio)methyltetrahydropyran-2-one.
According to a further feature of the present invention there is provided a
racemate comprising the compounds of Formulae (14) and (17):
##STR37##
wherein: Z is --H or a protecting group; and
Y formyl or protected formyl.
According to a further feature of the present invention there is provided a
racemate comprising the compounds of the Formulae (15) and (16):
##STR38##
wherein:
Z is --H or a protecting group; and
Y formyl or protected formyl.
According to a further feature of the present invention there is provided a
dihydropyran-2-one of the Formula (18):
##STR39##
wherein: Z is --H or a protecting group; and
Y is formyl or protected formyl.
According to a further feature of the present invention there is provided a
resolved dihydropyran-2-one of the Formula (19):
##STR40##
wherein: Z is --H or a protecting group; and
Y is formyl or protected formyl.
According to a further feature of the present invention there is provided a
racemate of dihydropyran-2-ones of Formula (2) wherein Y and Z are as
hereinbefore defined.
According to a further feature of the present invention there is provided a
pyran-2-one of the Formula (3) wherein Z and Y are as hereinbefore
defined.
According to a further feature of the present invention there is provided a
pyran-2-one of Formula (4) wherein Z and X are as hereinbefore defined,
provided that when Z is --H, X is not --Br or --Cl.
According to a further feature of the present invention there is provided a
pyran-2-one of Formula (5) wherein Z, W and X are as hereinbefore defined,
provided that when Z is --H and W is --COCH.sub.3, X is not --Br.
According to a further feature of the present invention there is provided a
pyran-2-one of Formula (6) wherein Z and W are as hereinbefore defined,
provided that when Z is --H, W is not --COCH.sub.3.
According to a further feature of the present invention there is provided a
pyran-2-one of Formula (7) wherein Z is a protecting group.
According to a further feature of the present invention there is provided a
pyran-2-one of Formula (8) wherein Z is a protecting group and X and W are
as hereinbefore defined provided that when Z is --H and W is --COCH.sub.3,
X is not --Br.
According to a further feature of the present invention there is provided a
pyran-2-one of Formula (10) wherein Z and W are as hereinbefore defined.
According to a further feature of the present invention there is provided a
pyran-2-one of Formula (11) wherein Z and W are as hereinbefore defined,
provided that when Z is --H, W is not --H or --COCH.sub.3.
According to a further feature of the present invention there is provided a
pyran-2-one of Formula (13) wherein Y is formyl or protected formyl.
The invention may be illustrated by the following:
EXAMPLE 1
i) 3-Acetyl-6-methyl-4-hydroxypyran-2-one may be deacylated by reaction
with 90% sulphuric acid at 130.degree. C. to give 6-methyl-4-hydroxy
pyran-2-one;
ii) 6-Methyl-4-hydroxypyran-2-one may be oxidised with selenium dioxide in
boiling diglyme to give 6-formyl-4-hydroxypyran-2-one;
iii) The formyl group in 6-formyl-4-hydroxypyran-2-one may be protected by
reaction with methanol in the presence of dry hydrogen chloride to give
6-dimethoxymethyl-4-hydroxypyran-2-one;
iv) 6-Dimethoxymethyl-4-hydroxypyran-2-one may be reduced in methanol with
hydrogen in the presence of a palladium on carbon catalyst to give
6-dimethoxymethyl-5,6-dihydro-4-hydroxy-pyran-2-one;
v) 6-Dimethyoxymethyl-5,6-dihydro-4-hydroxypyran-2-one may be reduced in
methanol with hydrogen in the presence of a Raney nickel catalyst to give
6-dimethoxymethyl-4-hydroxytetrahydropyran-2-one;
vi) 6-Dimethoxymethyl-4-hydroxytetrahydropyran-2-one may be resolved in
tetrahydrofuran by transesterification with vinyl acetate in the presence
of a lipase at 40.degree. C. according to the scheme:
##STR41##
after removing the lipase by filtration and evaporating the volatile
solvents by vacuum distillation the crude product may be chromatographed
on silica using a mixture of ethylacetate and dichloromethane to obtain
the 4-hydroxytetrahydropyran-2-one enantiomer represented by (A).
vii) Repeating vi) above using the trans racemate of
6-dimethoxymethyl-4-hydroxytetrahydropyran-2-one produces the trans
isomers (A) and (C).
EXAMPLE 2
i) 6-Methyl-4-hydroxypyran-2-one as produced in Example 1 may be brominated
with N-bromosuccinimide, in carbon tetrachloride in the presence of
ultraviolet radiation to give 6-dibromomethyl-4-hydroxy-pyran-2-one.
ii) 6-Dibromomethyl-4-hydroxypyran-2-one may be reacted with ethanol in the
presence of silver nitrate to give 6-diethoxymethyl-4-hydroxpyran-2-one.
iii) 6-Diethoxymethyl-4-hydroxypyran-2-one may be further converted
according to the method of Example 1 into Compound (E):
##STR42##
EXAMPLE 3
i) 3-Acetyl-4-hydroxy-6-methylpyran-2-one may be brominated with
N-bromosuccinimide in carbon tetrachloride at 40.degree. C. in the
presence of ultraviolet radiation to give
3-acetyl-6-dibromomethyl-4-hydroxy pyran-2-one.
ii) 3-Acetyl-4-hydroxy-6-bromomethylpyran-2-one may be reacted with ethanol
in the presence of silver nitrate to give
3-acetyl-6-diethoxymethyl-4-hydroxypyran-2-one.
iii) 3-Acetyl-6-diethoxymethyl-4-hydroxypyran-2-one may be reacted with
aqueous acid to give 3-acetyl-6-formyl-4-hydroxypyran-2-one.
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